Public and private human T-cell clones respond differentially to HCMV antigen when boosted by CD3 copotentiation
| Autor: | Svetomir N. Markovic, Shari L. Sutor, Michele M. Hoffmann, Christopher A. Parks, Megan Abergel, Adam G. Schrum, Larry R. Pease, Laura R.E. Becher, Wendy K. Nevala, Diana Gil |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Human cytomegalovirus Immunobiology and Immunotherapy T cell CD3 Cytomegalovirus CD8-Positive T-Lymphocytes Stimulus (physiology) Biology 03 medical and health sciences 0302 clinical medicine Immune system Antigen HLA-A2 Antigen medicine Humans T-cell receptor Hematology medicine.disease Clone Cells 030104 developmental biology medicine.anatomical_structure Cytomegalovirus Infections Immunology biology.protein 030215 immunology |
| Zdroj: | Blood Adv |
| ISSN: | 2473-9537 2473-9529 |
| DOI: | 10.1182/bloodadvances.2020002255 |
| Popis: | Human cytomegalovirus (HCMV) induces long-lasting T-cell immune responses that control but do not clear infection. Typical responses involve private T-cell clones, expressing T-cell antigen receptors (TCRs) unique to a person, and public T-cell clones with identical TCRs active in different people. Here, we report the development of a pretherapeutic immunostimulation modality against HCMV for human T cells, CD3 copotentiation, and the clonal analysis of its effects in recall assays at single-cell resolution. CD3 copotentiation of human T cells required identification of an intrinsically inert anti-CD3 Fab fragment that conditionally augmented signaling only when TCR was coengaged with antigen. When applied in recall assays, CD3 copotentiation enhanced the expansion of both public and private T-cell clones responding to autologous HLA-A2(+) antigen-presenting cells and immunodominant NLVPMVATV (NLV) peptide from HCMV pp65 protein. Interestingly, public vs private TCR expression was associated with distinct clonal expansion signatures in response to recall stimulus. This implied that besides possible differences in their generation and selection in an immune response, public and private T cells may respond differently to pharmacoimmunomodulation. Furthermore, a third clonal expansion profile was observed upon CD3 copotentiation of T-cell clones from HLA-A2(−) donors and 1 HLA-A2(+) presumed-uninfected donor, where NLV was of low intrinsic potency. We conclude that human T-cell copotentiation can increase the expansion of different classes of T-cell clones responding to recall antigens of different strengths, and this may be exploitable for therapeutic development against chronic, persistent infections such as HCMV. |
| Databáze: | OpenAIRE |
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